Cell-mediated immune reactions depend on direct interactions between T-lymphocytes and cells bearing the antigen that T-cells recognize. T cells recognize body cells infected with viruses, which replicate inside cells using the synthetic machinery of the cell itself. Antigens derived from the replication of a virus, however, are present on the surface of infected cells (by MHC class I), where they are recognized by cytotoxic T-cells (CD8+ T-cells), which may then control the infection by killing the cells before the virus replication is complete.
Vaccines for prophylaxis of viral infections are usually live attenuated organisms with reduced pathogenicity that would stimulate protective immunity. Foreign proteins of a live virus that is used as a live attenuated vaccine are recognized and processed in the endoplasmic reticulum (ER) lumen of antigen presenting cells (APCs) when the virus replicates to form an endogenous processing peptide. The process includes antigen modification and proper digestion. However, a live attenuated vaccine, especially in RNA virus, has a quite strong tendency to recover toxicity and virulence. For example, the toxicity of an infectious laryngotracheitis virus (ILTV) recovers both in vaccine or attenuated strains. Besides, multiple passages of a virus should be operated. Therefore, the ability to evoke an immune response is discredited. It is a time-consuming job to develop a live attenuated vaccine.
To prevent the recovery of a live attenuated vaccine, gene deficient vaccines are developed, such as Aujeszky's disease vaccines, gI negative vaccines, and PRV marker vaccines.
Viruses or bacteria of vaccina or fowlpox are used as vectors for carrying the genes of antigens. Through recombinant DNA technology, the time for development of a good vaccine is reduced and multiple serotypes of vaccine can be achieved at the same time. Examples of such vaccines are fowlpoxvirus and Salmonella vector systems and Syntro Vet (US) gene recombinant vaccines. On the other hand, when a microorganism, especially an RNA virus, is used as a vector vaccine, the microorganism would derive a new species or a new strain. The safety of such vector vaccines is again challenged. In addition, traditional recombinant subunit vaccines are usually helpless in triggering a cell-mediated immune response. They are exogenous antigens, which are taken into macrophages, dendritic cells and B lymphocytes. Peptides of immunogen epitopes from exogenous antigens are generated after internalization of antigens by APCs via fluid phase pinocytosis or membrane-bound receptors. The peptides are then generated in the endosomal compartments of the APCs and sorted by empty MHC class II molecules to form peptide-MHC class II complexes based on the affinities between MHC class II molecules and peptides. The peptide-MHC class II complexes are then translocated to the surface of the APCs, where they are recognized by CD4+ T-cells. However, subunit type proteins recognized by CD8+ T-cells cannot be used efficiently as vaccines because once administration, they are internalized in endosomal compartments, where they are likely to be either extensively degraded or fail to interact with the MHC class I pathway. Furthermore, CD4+ cells (Th cells) can activate both humoral immunity and cell-mediated immune response by Th1 and Th2 helper T-cells, respectively. Th1 and Th2 cells regulate each other for the balance of humoral immunity and cell-mediated immune response.
Viruses that infect immunological cells such as T-cell, B-cell, dendritic cell, monocyte, or macrophage have been discovered and investigated. Examples of such swine infected viruses are porcine reproductive and respiratory syndrome virus, circovirus type II, and human infected virus, human immunodeficiency virus. Such viruses shut down the ability of recognition of foreign proteins as antigens in the antigen presenting cells. The immunological cells cannot evoke an immunization response and carry the viruses. The animals that have been infected by these types of viruses are easily secondarily infected by other pathogens. It is a pity that a useful vaccine targeting virus-infected immunological cells is still lacking.
In particular, porcine reproductive and respiratory syndrome virus (PRRSV) results in high losses in animal husbandry every year. The virus infects macrophages (in the alveolar and spleen), brain microglia and monocytes, and exists in the blood and organs of the infected animals. Antibodies have little effect on the virus and even stimulate mutations of the virus. In the mechanism of antibody dependent enhancement (ADE), the use of antibodies leads to more severe infections. About 50 to 80% of pigs are infected by such virus. Generally, the animals infected by the virus have no significant symptoms, but the immunity of the infected animals is reduced. This leads to a decrease of weight gain and an increase in the death rate due to the secondary infection. PRRSV is an RNA virus. Not only swine but ducks can be infected by PRRSV as well. A live attenuated vaccine against PRRSV was developed. However, mutation of the viruses in the live vaccine often occurs. Fortunately, recent reports of HIV vaccine development strongly indicate that cytotoxic T-cells (CTLs) are essential for controlling HIV infection. (Hanne G-S et al 2000, Journal of virology, vol. 74, No. 4. p. 1694-1703). To develop a safe and effective PRRS vaccine is urgently desired.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies, especially in connection with development of T-cell vaccines against virus infection.